The chicken or the egg? Unravelling the role of vascular remodelling in HFpEF

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ syndrome in which symptoms of heart failure occur despite a preserved ejection fraction (≥50%).Impaired ventricular relaxation and elevated filling pressures, particularly during exertion, contribute to dyspnoea and exercise intolerance.Predisposing risk factors, including obesity, hypertension, diabetes and ageing, also promote systemic inflammation, reduced nitric oxide (NO) bioavailability and arterial stiffening, thereby linking vascular pathology to ventricular dysfunction.Vascular pathology may therefore contribute to HFpEF progression rather than develop only as a parallel consequence.Conduit artery wall thickening and fibrosis can increase afterload, whereas endothelial and vascular smooth muscle dysfunction can attenuate vasodilator and vasoconstrictor responsiveness, collectively worsening diastolic dysfunction and exercise intolerance.HFpEF is a heterogeneous syndrome with several phenotypes, one of which is a cardiometabolic form driven by metabolic and hypertensive stress.Other forms of HFpEF may be driven by ageing, cardiac amyloidosis or chronic hypertension independent of metabolic disease.Animal models therefore replicate only selected features of the human syndrome.The established high-fat diet (HFD) plus N ω -nitro-l-arginine methyl ester (l-NAME) 'two-hit' mouse model reproduces several features of cardiometabolic HFpEF, but its vascular phenotype had not been comprehensively described, limiting its application to the